Day: December 27, 2018

Novel phytochemical-antibiotic conjugates as multitarget inhibitors of Pseudomononas aeruginosa GyrB/ParE and DHFR

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BACKGROUND: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets.
METHODS: In line with our previous work on phytochemical-antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical-antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions.
RESULTS: Evaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues.
CONCLUSION: This new design concept of hybrid “phyto-drug” scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery.

Synergistic Antibacterial Effects of Chitosan-Caffeic Acid Conjugate against Antibiotic-Resistant Acne-Related Bacteria

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The object of this study was to discover an alternative therapeutic agent with fewer side effects against acne vulgaris, one of the most common skin diseases. Acne vulgaris is often associated with acne-related bacteria such as Propionibacteriumacnes, Staphylococcusepidermidis, Staphylococcusaureus, and Pseudomonasaeruginosa. Some of these bacteria exhibit a resistance against commercial antibiotics that have been used in the treatment of acne vulgaris (tetracycline, erythromycin, and lincomycin). In the current study, we tested in vitro antibacterial effect of chitosan-phytochemical conjugates on acne-related bacteria. Three chitosan-phytochemical conjugates used in this study exhibited stronger antibacterial activity than that of chitosan (unmodified control). Chitosan-caffeic acid conjugate (CCA) showed the highest antibacterial effect on acne-related bacteria along with minimum inhibitory concentration (MIC; 8 to 256 μg/mL). Additionally, the MIC values of antibiotics against antibiotic-resistant P. acnes and P.aeruginosa strains were dramatically reduced in combination with CCA, suggesting that CCA would restore the antibacterial activity of the antibiotics. The analysis of fractional inhibitory concentration (FIC) indices clearly revealed a synergistic antibacterial effect of CCA with antibiotics. Thus, the median sum of FIC (∑FIC) values against the antibiotic-resistant bacterial strains ranged from 0.375 to 0.533 in the combination mode of CCA and antibiotics. The results of the present study suggested a potential possibility of chitosan-phytochemical conjugates in the control of infections related to acne vulgaris. (Mar Drugs. 2017 Jun 8;15(6).)